Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents

ABSTRACT

The low aqueous solubility of roflumilast in parenteral preparations and topical emulsions, suspensions, gels or solutions can be improved by including a blend of water-miscible solvents in the pharmaceutical composition. The blend of water-miscible solvents can include diethylene glycol monoethyl ether (Tradename Transcutol®; abbreviated DEGEE) and water. The ratio of diethylene glycol monoethyl ether to water is from 1:10 to 20:1. The resulting composition has improved bioavailability and efficacy and can be used to inhibit phosphodiesterase 4 in a patient in need of such treatment.

This application is a continuation from U.S. Ser. No. 15/712,900 filedSep. 22, 2017, the disclosure of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The invention pertains to pharmaceutical compositions of roflumilast inblends of water-miscible, pharmaceutically acceptable solvents. Moreparticularly, the invention involves the discovery that roflumilast, adrug with poor water solubility, exhibits unexpectedly high solubilityin such solvent blends.

BACKGROUND OF THE INVENTION

Roflumilast is known to be suitable as a bronchial therapeutic agent aswell as for the treatment of inflammatory disorders. Compositionscontaining roflumilast are used in human and veterinary medicine andhave been proposed for the treatment and prophylaxis of diseasesincluding but not limited to: inflammatory and allergen-induced airwaydisorders (e.g. bronchitis, asthma, COPD); dermatoses (e.g.proliferative, inflammatory and allergen induced skin disorders), andgeneralized inflammations in the gastrointestinal region (Crohn'sdisease and ulcerative colitis).

Roflumilast and its synthesis were described in U.S. Pat. No. 5,712,298(the “'298 patent”), incorporated herein by reference.* It has long beenrecognized that pharmaceutical compounds having phosphodiesterase(PDE)-inhibiting properties, such as roflumilast, are useful fortreating psoriasis and atopic dermatitis ('298 patent, col 11 lines52-61) and other chronic inflammatory and allergen-induced dermatoses.For treatment of such dermatoses, roflumilast emulsions, suspensions,gels or solutions for topical application have been described ('298patent, col 12, lines 37-64). Although oral tablets of roflumilast havebeen commercialized, the low aqueous solubility of the compound has beenreported to be only 0.53 mg/l at 21° C. in WO95/01338 (corresponding tothe '298 patent and incorporated herein by reference). This low aqueoussolubility has been problematic for the development of parenteralpreparations and topical emulsions, suspensions, gels or solutionscontaining water. In U.S. Pat. No. 9,205,044 (incorporated herein byreference), the poor water solubility of roflumilast was overcome byusing an alkoxylated fat, specifically polyoxyethylated12-hydroxystearic acid, as a co-solvent for parenteral administration.In EP 1511516B1 (corresponding to published U.S. application Ser. No.14/075,035 incorporated herein by reference), the low water solubilityof roflumilast was overcome in topical emulsion (cream) formulations byformulating with polyethylene glycol 400 (PEG 400) in concentrationsover 62% (w/w) while keeping water weight percentages under 10%. *Unlessotherwise indicated, references incorporated herein by reference areincorporated in their entireties for all purposes.

Topical application of potent pharmacological agents like roflumilastfor treating skin diseases has been found to provide superior delivery,lower systemic exposure and greater ease of use for patients. Themolecular structure of the compound ultimately dictates the ability ofthe drug to cross the epithelium of the tissue to which the product isapplied. For cutaneous application, selection of the components of theformulation dictates the maximum skin permeation that the formulator canachieve. Creams, lotions, gels, ointments, foams and solutions are justa few of the more familiar forms of topical roflumilast formulationsthat often contain completely dissolved active pharmaceuticalingredients (API) for application to the skin as disclosed in the '298patent (col 12, lines 37-64). For treatment of such dermatoses,roflumilast emulsions, suspensions, gels or solutions for topicalapplication have been described, although the low solubility of thecompound has limited those applications.

Several approaches have been proposed for enhancing the solubility ofactive ingredients with low aqueous solubility. These approaches includeparticle size reduction, hydrotrophy, precipitation inhibitors (e.g.HPMC, PVP, PVA, PEG) complexation, solvent deposition, alteration of pH,lyophilization, surfactants, co-solvency, micro emulsions, soliddispersion and solvate formation. WO 2013/030789 discloses PDE-IVinhibitor with poor water solubility in combination with a binderselected from a saccharide (e.g. sucrose, lactose, starches,microcrystalline cellulose, low-viscosity hydroxypropyl cellulose and/ora hydroxypropylmethyl cellulose), protein (e.g. gelatin) or syntheticpolymer (e.g. polyethylene glycol, polyvinyl acetate, polyvinyl alcoholand propylene glycol). In U.S. Pat. No. 9,205,044 (incorporated hereinby reference), the poor water solubility of roflumilast was overcome byusing alkoxylated fat, specifically polyoxyethylated 12-hydroxystearicacid, as a co-solvent. In EP 1511516B1 (corresponding to published U.S.application Ser. No. 14/075,035 incorporated herein by reference), thelow water solubility of roflumilast was overcome in topical emulsionformulations (creams) by formulating with polyethylene glycol 400 (PEG400) in concentrations over 62% (w/w) while keeping water weightpercentages under 10%. U.S. Pat. No. 7,951,398 (incorporated herein byreference) discloses a solid dispersion of roflumilast, which isindicated as a poorly soluble drug, wherein roflumilast is dispersed ina matrix comprising fatty alcohol, triglyceride and fatty acid ester athigh temperature, and then cooled and granulated with a hydrophilicpolymer. U.S. Pat. No. 6,074,670 discloses a composition of fenofibrate,which is a poorly soluble drug, which has improved dissolution. Thecomposition includes a hydrophilic polymer and a surfactant, wherein thefenobibrate was granulated with solution of a hydrophilic polymer suchas polyvinylpyrrolidone which results in an improved dissolutionprofile. U.S. Pat. No. 8,431,154 (incorporated herein by reference)discloses a composition of Roflumilast with improved release andimproved pharmacokinetic profile by using an aqueous solution ofpolyvinylpyrrolidone (PVP) for granulation of roflumilast by preparing asolid solution or solid dispersion. Published U.S. application Ser. No.14/114,541 (incorporated herein by reference) discloses that novel PI3Kinhibitors can be combined with soluble macromolecular entities, such ascyclodextrin and suitable derivatives thereof or polyethyleneglycol-containing polymers in order to improve their solubility,dissolution rate, taste-masking, bioavailability and/or stability.

WO 2015/132708 discloses the use of a multiparticulate compositioncontaining roflumilast and an inert component. The inert component isprepared by granulation and then combined with the roflumilast resultingin a composition with improved dissolution. The composition preferablyincludes a polyvinyl alcohol as part of the inert component,

One technique for increasing solubility of an active ingredient has beento blend an alcohol or a glycol with water to create a solvent blendthat is less polar than water. Because pharmaceutically acceptablealcohols, such as ethanol or isopropyl alcohol, are not desirableexcipients for topical application to inflammatory dermatoses due to thetendency to further irritate inflamed skin, propylene glycol is aco-solvent frequently used in topical creams and gels for the treatmentof psoriasis or atopic dermatitis. Propylene glycol (abbreviated PG) hasbeen used to increase the solubility of corticosteroids in topical gels,lotions and creams that tend to contain greater than 20% water andvolatiles and/or less than 50% hydrocarbons, waxes, or polyols (USP<1151> Definition of Topical Emulsion). Another solvent chemically verysimilar to PG that was first used in an FDA-approved topical product in2005, is diethylene glycol monoethyl ether (Tradename TRANSCUTOL®) andabbreviated DEGEE. Diethylene glycol monoethyl ether is used as avehicle and as a solubilizer for preparing pharmaceutical compositions(for example, see U.S. application Ser. Nos. 14/242,973; 12/846,079 and15/376,345, incorporated herein by reference). Diethylene glycolmonoethyl ether is also used as a skin permeability enhancer (U.S.application Ser. Nos. 15/260,554 and 15/297,998, incorporated herein byreference) and as a surfactant (U.S. Pat. No. 9,649,302, incorporatedherein by reference). Although PG has been used in many more FDAapproved topical products for decades longer than DEGEE, the twosolvents are remarkably similar as shown in Table 1. However, thesesolvents have different effects on the solubility and skin permeabilityof different active ingredients.

TABLE 1 Comparison of two pharmaceutically acceptable glycols for use intopical products. Property DEGEE PG Molecular Formula C₆H₁₄O₃ C₃H₈O₂Molar Mass g/mole 134.18 76.1 Density g/ml at 20° C. 0.989 1.036 MeltingPoint −76° C. −59° C. Boiling Point 198-210° C. 187-188° C.Octanol-Water Partition −0.43 −0.92 Coefficient (log P)

Minghetti et. al. (J. Pharm. Sci. 96(4)814-823, 2007) determined thesolubility of four salts of diclofenac in neat PG and neat DEGEE andthis solubility data is summarized in Table 2.

TABLE 2 Solubility data for four salts of diclofenac taken from P.Minghetti et. al, J. Pharm. Sci 96, 814-823) Solubility in SolubilityPharmaceutical Active DEGEE (μg/mL) in PG (μg/mL) Sodium Diclofenac660 + 70 567 + 31 Potassium Diclofenac 709 + 52 898 + 79 DiethylamineDiclofenac 279 + 10 384 + 14 Epolamine Diclofenac 430 + 0  637 + 60

Although both solvents are considered safe for topical application up toand beyond about 50 weight percent, pharmaceutical formulations usuallylimit the amount of DEGEE or PG to about 30% due to irritation seen in asubset of patients. Thus, these glycols are almost always blended withwater when formulating topical gels or emulsions (creams or lotions).When blending two solvents the ideal solubility of any blend can becalculated based on the solubility of the active ingredient in each ofthe separate solvents. The calculated “ideal” solubility will best agreewith the observed solubility when the physical properties of the twosolvents are closely aligned. The J. W. Lorimer publication on thethermodynamics of solubility in mixed solvent systems (Pure & Appl.Chem. 65(2)183-191, 1993) showed exact correlation between ideal andmeasured solubility of NaCl when dissolved in blends of water (H₂O) anddeuterium oxide (D20) and reasonable correlations for NaCl data inblends of water and ethylene glycol. For the blend of water and ethyleneglycol, the poorest correlation between calculated “ideal” solubilityand observed solubility occurred at equimolar blends of the two solventswith the observed saturation solubility being 18-fold lower than thecalculated ideal solubility (J. Solution Chem., 14, 635 (1985)). Lorimeruses classical thermodynamics to derive the ideal solubility (shown asln(m_(s) ⁽¹²⁾/m°) in the paper) based on the chemical potential of thesolute (API) in solvent which has a linear correlation to mole fractionof the solvent blend.

The ability to calculate the expected solubility at any ratio of thesolvent blend after experimentally determining drug solubility in eachof the two neat solvents facilitates formulation of a topical product.Usually a target concentration has been determined based on the potencyof the API. Highly potent drug active ingredients, such as some of thecorticosteroids or calcipotriene, will have target concentrations in atopical product of 0.05% to 0.5%. Most topical products will be around2%. Since maximum thermodynamic driving force across the skin occurs atsaturation, the skilled formulator will want to know saturation drugconcentrations in solvent blends over a range of solvent blend ratios.By calculating ideal solubility values before setting up a full matrixof experimental solubility determinations, the number of experiments canbe reduced from a few hundred to less than 100 observed saturated drugsolubility determinations.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has been discovered thatsurprisingly high concentrations of roflumilast can be dissolved insolvent blends of diethylene glycol monoethyl ether (DEGEE) and water.This dramatically increased solubility of roflumilast was maintainedwhen the solvent blend was formulated with up to 0.5% roflumilast in anemollient cream.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one figure executed incolor. Copies of this patent or patent application publication withcolor figures will be provided by the Office upon request and payment ofthe necessary fee.

FIG. 1 shows a Microscopic View of a sample of formulation 1 using apolarized light microscope equipped with a 10× objective.

FIG. 2 shows a Microscopic View of a sample of formulation 2 using apolarized light microscope equipped with a 10× objective.

FIG. 3 shows a Microscopic View of a sample of formulation 3 using apolarized light microscope equipped with a 10× objective. The bluearrows indicate five of the largest undissolved roflumilast particles inthe photomicrographs of these five creams

FIG. 4 shows a Microscopic View of a sample of formulation 4 using apolarized light microscope equipped with a 10× objective. The bluearrows indicate five of the largest undissolved roflumilast particles inthe photomicrographs of these five creams

FIG. 5 shows a Microscopic View of a sample of formulation 5 using apolarized light microscope equipped with a 10× objective. The bluearrows indicate five of the largest undissolved roflumilast particles inthe photomicrographs of these five creams.

DESCRIPTION OF THE INVENTION

Roflumilast is a compound of the formula (I)

wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is3,5-dichloropyrid-4-yl.

This compound has the chemical nameN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamid-e(INN: roflumilast). Roflumilast can be prepared by methods known in theart (e.g. see the '298 patent and U.S. application Ser. No. 14/075,035).

Diethylene glycol monoethyl ether is a compound of the formula (II)

The present invention is directed to pharmaceutical compositions ofroflumilast dissolved in blends of diethylene glycol monoethyl ether(DEGEE, Gattefosse Tradename TRANSCUTOL®) and water, optionallyincluding one or more pharmaceutically acceptable carriers. Any suitablegrade of TRANSCUTOL® can be used including TRANSCUTOL®P, TRANSCUTOL®HP,TRANSCUTOL®V and TRANSCUTOL®CG. This blend of DEGEE and water canundergo the addition of excipients and further processing to form arange of pharmaceutical dosage forms and maintain dissolved ormolecularly dispersed roflumilast over the shelf life of the drugproduct.

The present invention is particularly useful for topical formulations.The topical roflumilast pharmaceutical product formulations that couldbe based on DEGEE-water blends are defined in U.S. Pharmacopeia USP<1151> and include aerosols, foams, sprays, emulsions (which can also becalled creams, lotions, or ointments), gels (two phase or single phase),liquids, ointments, pastes, shampoos, suspensions, and systems. Theseare typical dosage forms containing pharmaceutically active ingredientsfor topical application to mammals, including humans.

Topical application refers to dosing the skin, hair or nails of apatient that will benefit from treatment with a pharmaceutical product.Topical can also mean application to the epithelium of the patient forlocalized delivery. This would include ophthalmic, ottic, oral mucosa,vaginal mucosa, rectal mucosa or urethral application of roflumlast. Thebroadest definition of topical would include using the epithelium of apatient as a route of administration to obtain therapeutic systemiclevels of the active ingredient. This definition of topical is oftenreferred to as transdermal delivery of therapeutic active ingredients.

DEGEE is often formulated as 10-30% (w/w), preferably 15-20% (w/w), intopical formulations. Likewise, water is formulated as about 20-90%(w/w) in topical products. For blends of DEGEE and water the ratio canrange from 1:10 to 20:1. Preferably the DEGEE:water ratio is 1:4 to 9:1in a formulation containing roflumilast.

Generally, DEGEE-water blends can be used to dissolve up to 2.0%roflumilast (in the finished product) or preferably up to 0.5%roflumilast (in the finished product). The finished product ispreferably in one of the following forms:

An oil-in-water emulsion: The topical product may be an emulsioncomprising a discrete hydrophobic phase and a continuous aqueous phasethat includes the DEGEE-water blend and optionally one or more polarhydrophilic excipients as well as solvents, co-solvents, salts,surfactants, emulsifiers, and other components. These emulsions mayinclude water-soluble or water-swellable polymers that help to stabilizethe emulsion.

A water-in-oil emulsion: The compositions may be formulations in whichroflumilast is incorporated into an emulsion that includes a continuoushydrophobic phase and an aqueous phase that includes the DEGEE-waterblend and optionally one or more polar hydrophilic carrier(s) as well assalts or other components. These emulsions may include oil-soluble oroil-swellable polymers as well as one or more emulsifier(s) that help tostabilize the emulsion.

For both oil-in-water and water-in-oil emulsions, order of addition maybe important. Roflumilast can be added pre-dissolved in the continuousaqueous phase containing the DEGEE-water blend. Likewise, roflumilastcan be pre-dissolved in the hydrophobic discrete phase of the emulsionthat is then mixed with the DEGEE-water blend and optional hydrophilicexcipients that do not contain the active ingredient. Roflumilast can bepre-dissolved in both the oil phase and water phase of the emulsion oradded pre-dissolved in DEGEE or a DEGEE-water blend after the emulsionhas been formed. Some emulsions undergo phase inversion over a specifictemperature range during cooling of the emulsion. Thus, roflumilast maybe added to a water-in-oil emulsion above the phase inversiontemperature, with the final drug product being an oil-in-water emulsionat controlled room temperature, or vice versa.

Thickened aqueous gels: These systems include the DEGEE-water blend withdissolved roflumilast and optionally one or more polar hydrophiliccarrier(s) such as hexylene glycol which has been thickened by suitablenatural, modified natural, or synthetic thickeners as described below.Alternatively, the thickened aqueous gels can be thickened usingsuitable polyethoxylate alky chain surfactants or other nonionic,cationic, or anionic systems.

Thickened hydroalcoholic gels: These systems include theDEGEE-water-alcohol blend with dissolved roflumilast and optionally oneor more polar hydrophilic carrier(s) such as hexylene glycol as thepolar phase which has been thickened by suitable natural, modifiednatural, or synthetic polymers such as described below. Alternatively,the thickened hydroalcoholic gels can be thickened using suitablepolyethoxylate alky chain surfactants or other nonionic, cationic, oranionic systems. The alcohol can be ethanol, isopropyl alcohol or otherpharmaceutically acceptable alcohol.

A hydrophilic or hydrophobic ointment: The compositions are formulatedwith a hydrophobic base (e.g. petrolatum, thickened or gelled waterinsoluble oils, and the like) and optionally have a minor amount of theDEGEE-water blend with dissolved roflumilast. Hydrophilic ointmentsgenerally contain one or more surfactants or wetting agents.

Solvents

Compositions of the present invention may include one or more solventsor co-solvents to obtain the desired level of active ingredientsolubility in the product. The solvent may also modify skin permeationor activity of other excipients contained in a topical product. Solventsinclude but are not limited to acetone, ethanol, benzyl alcohol, butylalcohol, diethyl sebacate, diethylene glycol monoethyl ether,diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropylalcohol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidinone, propylene glycol and SD alcohol.

Moisturizers

Compositions of the present invention may include a moisturizer toincrease the level of hydration. For emulsions, the moisturizer is oftena component of the discrete or continuous hydrophobic phase. Themoisturizer can be a hydrophilic material including humectants or it canbe a hydrophobic material including emollients. Suitable moisturizersinclude but are not limited to: 1,2,6-hexanetriol,2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetylesters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone,dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids,glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryloleate, glyceryl palmitate, glycol distearate, glycol stearate,isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene,medium-chain triglycerides, menthol, myristyl alcohol, octyldodecanol,oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanutoil, petrolatum, Plastibase-50W, and stearyl alcohol.

Surfactants and Emulsifiers

Compositions according to the present invention can optionally includeone or more surfactants to emulsify the composition and to help wet thesurface of the active ingredients or excipients. As used herein the term“surfactant” means an amphiphile (a molecule possessing both polar andnonpolar regions which are covalently bound) capable of reducing thesurface tension of water and/or the interfacial tension between waterand an immiscible liquid. Surfactants include but are not limited toalkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate,apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride,Ceteareth-6, Ceteareth-12, Ceteareth-15, Ceteareth-30, cetearylalcohol/ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-10phosphate, ceteth-2, ceteth-20, ceteth-23, choleth-24, cocamide ethersulfate, cocamine oxide, coco betaine, coco diethanolamide, cocomonoethanolamide, coco-caprylate/caprate, dicetyl phosphate, disodiumcocoamphodiacetate, disodium laureth sulfosuccinate, disodium laurylsulfoacetate, disodium lauryl sulfosuccinate, disodium oleamidomonoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23,laureth-4, lauric diethanolamide, lecithin, mehoxy PEG-16, methylgluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2,oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate,PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate,PEG-2 stearate, PEG-20 methyl glucose sesqustearate, PEG-22 methylether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate,PEG-45/dodecyl glycol copolymer, PEG-5 oleate, PEG-50 Stearate, PEG-54hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castoroil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate,Pegoxol 7 stearate, pentaerythritol cocoate, poloxamer 124, poloxamer181, poloxamer 182, poloxamer 188, poloxamer 237 poloxamer 407,polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fattyacid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenatedcastor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxylglyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate,PROMULGEN™ 12, propylene glycol diacetate, propylene glycol dicaprylate,propylene glycol monostearate, sodium xylene sulfonate, sorbitanmonooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2,steareth-20, steareth-21, steareth-40, tallow glycerides, andemulsifying wax.

Polymers and Thickeners

For certain applications, it may be desirable to formulate a topicalproduct that is thickened with soluble, swellable, or insoluble organicpolymeric thickeners such as natural and synthetic polymers or inorganicthickeners including but not limited to acrylates copolymer, carbomer1382, carbomer copolymer type B, carbomer homopolymer type A, carbomerhomopolymer type B, carbomer homopolymer type C, carboxy vinylcopolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan,guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,microcrystalline wax, and methylcellulose.

Additional Components

Compositions according to the present invention may be formulated withadditional components conventionally found in cosmetic andpharmaceutical topical products. Additional components include but arenot limited to antifoaming agents, preservatives, antioxidants,sequestering agents, stabilizers, buffers, pH adjusting solutions, skinpenetration enhancers, film formers, dyes, pigments, fragrances andother excipients to improve the stability or aesthetics of the product.In a preferred embodiment, hexylene glycol is added to inhibit changesin particle size distribution over the shelf life of the composition.Hexylene glycol can be added between 0.1% and 20% on a weight/weightbasis, preferably between 0.25% and 8% on a weight/weight basis and mostpreferably between 0.5% and 2% on a weight/weight basis.

Compositions according to the present invention may be formulated withadditional active agents depending on the condition to be treated. Theadditional active agents include but are not limited to Anthralin(dithranol), Azathioprine, Tacrolimus, Coal tar, Methotrexate,Methoxsalen, Salicylic acid, Ammonium lactate, Urea, Hydroxyurea,5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine,Mycophenolate mofetil, Fumaric acid esters, Corticosteroids (e.g.Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone,Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide,Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide,Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate,Prednisone), Corticotropin, Vitamin D analogues (e.g. calcipotriene,calcitriol), Acitretin, Tazarotene, Cyclosporine, Resorcinol,Colchicine, Adalimumab, Ustekinumab, Infliximab, bronchodialators (e.g.beta-agonists, anticholinergics, theophylline), and antibiotics (e.g.erythromycin, ciprofloxacin, metronidazole).

Administration and Dosage

The compositions according to the present invention can be administeredby any suitable administration route including but not limited to oral,rectal, parenteral (e.g. intradermal, subcutaneous, intramuscular,intravenous, intramedullary, intra arterial, intrathecal, epidural)ocular, inhalation, nebulization, cutaneously (topically),transdermally, and mucosally (e.g. sublingual, buccal, nasally). In apreferred embodiment, the composition is administered topically.

Suitable pharmaceutical dosage forms include but are not limited toemulsions, suspensions, sprays, oils, ointments, fatty ointments,creams, pastes, gels, foams transdermal patches and solutions (e.g.injectable, oral).

The composition preferably contains roflumilast, salts of roflumilast,the N-oxide of roflumilast or salts thereof in an amount of 0.005-2%w/w, more preferably 0.05-1% w/w, and most preferably 0.1-0.5% w/w perdosage unit.

The composition preferably contains diethylene glycol monoethyl ether inan amount of between 5% and 50% w/w, more preferably between 20% and 30%w/w and most preferably between 22.5% and 27.5% w/w.

The composition can be administered one or more times per day,preferably the composition is administered 1-2 times per day.

The composition can be used in veterinary and in human medicine for thetreatment and prevention of all diseases regarded as treatable orpreventable by using roflumilast, including but not limited to acute andchronic airway disorders; proliferative, inflammatory and allergicdermatoses; disorders which are based on an excessive release of TNF andleukotrienes; disorders of the heart which can be treated by PDEinhibitors; inflammations in the gastrointestinal system or centralnervous system; disorders of the eye; arthritic disorders; and disorderswhich can be treated by the tissue-relaxant action of PDE inhibitors.Preferably, the composition is used to treat proliferative, inflammatoryand allergic dermatoses such as psoriasis (vulgaris), eczema, acne,Lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars,discoid lupus erythematosus, and pyodermias.

The following examples are provided to enable those of ordinary skill inthe art to make and use the methods and compositions of the invention.These examples are not intended to limit the scope of what the inventorsregard as their invention. Additional advantages and modifications willbe readily apparent to those skilled in the art.

Example 1

Roflumilast (Batch A14367P from Interquim S.A.), 0.0061 grams, wasweighed into a liquid scintillation vial. PG (propylene glycol, SpectrumChemical lot IEC0004) was added dropwise with mixing to the vialcontaining roflumilast. After mixing each addition of PG, the tightlycapped vial was returned to a water bath set at 25° C. It required1.9332 grams of PG to completely dissolve the 0.0061 grams ofroflumilast which equals the observed saturation solubility of 0.3 w/w %roflumilast in PG at 25° C. The cited value of 0.53 mg/l (at 21° C.) inWO95/01338 was used as the observed value for saturation solubility ofroflumilast in water which equals 0.000053 w/w %. Using the equations ofLorimer, the observed saturation solubility in PG of 0.3% roflumilastand the observed saturation solubility in water of 0.000053%, thecalculated ideal solubility of roflumilast in equimolar PG:Water is0.0040 w/w %.

2.3200 grams of an equimolar blend of PG (Spectrum Chemical lot IEC0004)and distilled water was prepared and added to a scintillation vialcontaining 0.0012 grams of roflumilast (Batch A14367P from InterquimS.A.). After equilibrating to 25° C. the roflumilast completelydissolved to form a 0.052% solution. An equimolar blend is 80.7% PG and19.3% water on a weight/weight percent basis. The addition of 2.2696grams of equimolar PG:Water did not completely dissolve 0.0017 grams ofroflumilast at 25° C. (0.075% roflumilast). The experimentallydetermined, observed saturation solubility of roflumilast equimolarPG:Water at 25° C. was 0.06 w/w %.

At 25° C. the observed saturation solubility of roflumilast in equimolarPG:Water was 15-fold greater than the calculated ideal solubility ofroflumilast in equimolar PG:Water blends (80.7:19.3 PG:Water w/w).

Example 2

Roflumilast (Batch A14367P from Interquim S.A.), 0.0205 grams, wasweighed into a liquid scintillation vial. DEGEE (Transcutol P, lot146063, Gattefosse) was added dropwise with mixing to the vialcontaining roflumilast. After mixing each addition of DEGEE, the tightlycapped vial was returned to a water bath set at 25° C. It required0.2699 grams of DEGEE to completely dissolve the 0.0205 grams ofroflumilast which equals an observed saturation solubility of 7.1 w/w %roflumilast in DEGEE at 25° C. The cited value of 0.53 mg/l (at 21° C.)in WO95/01338 was used as the observed value for saturation solubilityof roflumilast in water which equals 0.000053 w/w %. Using the equationsof Lorimer, the observed saturation solubility in DEGEE of 7.1%roflumilast and the observed saturation solubility in water of0.000053%, the calculated ideal solubility of roflumilast in equimolarDEGEE:Water is 0.019 w/w %. 0.0111 grams of roflumilast (Batch A14367Pfrom Interquim S.A.) was weighed into a liquid scintillation vial. Anequimolar blend of DEGEE (Transcutol P, lot 146063, Gattefosse) anddistilled water was prepared and added dropwise with mixing to the vialcontaining roflumilast. An equimolar blend is 88.3% DEGEE and 11.7%water on a weight/weight percent basis. After mixing each addition ofequimolar DEGEE:Water, the tightly capped vial was returned to a waterbath set at 25° C. 0.0111 grams of roflumilast did not dissolve afteraddition of 0.2337 grams of equimolar DEGEE:Water (4.53% roflumilast)but did dissolve after the addition of 0.2477 grams of equimolarDEGEE:Water (4.29% roflumilast). The experimentally determinedsaturation solubility of roflumilast equimolar DEGEE:Water at 25° C. wasobserved to be 4.4 w/w %.

At 25° C. the observed saturation solubility of roflumilast in equimolarDEGEE:Water was 232-fold greater than the calculated ideal solubility ofroflumilast in equimolar DEGEE:Water blends (88.3:11.7 DEGEE:Water w/w).

Example 3

0.5% roflumilast creams were prepared according to the followingformulations. After at least one month of storage in a tightly closedglass container, a thin smear of cream was loaded onto a glassmicroscope slide and a coverslip was placed on the sample. TheMicroscopic View of the sample using a polarized light microscopeequipped with a 10× objective was obtained (FIGS. 1-5 ). The MicroscopicView photomicrographs were examined to determine if undissolvedroflumilast was present in the cream. The blue arrows indicate five ofthe largest undissolved roflumilast particles in the photomicrographs ofthese five creams. Only the two creams containing Transcutol (25%) didnot contain undissolved active.

Formulation 1 Roflumilast 0.5% w/w White Petrolatum 10.0% w/w IsopropylPalmitate 5.0% w/w Crodafos ™ CES* 10.0% w/w Hexylene glycol 8.0% w/wN-methyl pyrrolidone 12.0% w/w Diethylene glycol monoethyl 25.0% w/wether (Transcutol P) Methylparaben 0.2% w/w Propylparaben 0.05% w/wPurified Water q.s. ad 100 (29.25%) *(Tradename for the Croda emulsifierblend of ceteary alcohol, dicetyl phosphate and ceteth-10 phosphate)

Formulation 2 Roflumilast 0.5% w/w White Petrolatum 10.0% w/w IsopropylPalmitate 5.0% w/w Crodafos ™ CES 10.0% w/w Hexylene glycol 2.0% w/wDiethylene glycol monoethyl 25.0% w/w ether (Transcutol P) Methylparaben0.2% w/w Propylparaben 0.05% w/w Purified Water q.s. ad 100 (47.25%)

Formulation 3 Roflumilast 0.5% w/w Glycerol Monostearate 8.0% w/wEmulgade ® A6** 4.0% w/w PEG 400 62.5% w/w Purified Water q.s. ad 100(25.0%) **(Tradename for the BASF emulsifier blend of Ceteareth-6 andStearyl Alcohol)

Formulation 4 Roflumilast 0.5% w/w Diisopropyl Adipate 15.0% w/w POE-7Cocoyl Glycerides 13.5% w/w Cetyl Alcohol 5.0% w/w Parafin 1.0% w/wLanolin 2.0% w/w Methyl Paraben 0.2% w/w PEG 400 3.0% w/w Xanthan Gum0.3% w/w Disodium EDTA 0.1% w/w Solan ™-75 PA*** 3.0% w/w Purified Waterq.s. ad 100 (56.4%) ***(Tradename for the Croda emulsifier PEG-75Lanolin)

Formulation 5 Roflumilast 0.5% w/w Diethyl Sebacate 10.0% w/w LightMineral Oil 0.7% w/w Sorbitan Monooleate 0.1% w/w Propylene glycol 7.5%w/w Methylparaben 0.17% w/w Propylparaben 0.03% w/w Edetate Disodium0.05% w/w Pemulen TR-1 0.4% w/w Carbopol 981 0.6% w/w 1N sodiumhydroxide 3.0% w/w Purified Water q.s. ad 100 (76.95%)

1. A topical, pharmaceutical, oil in water emulsion comprisingroflumilast and a blend of water-miscible, pharmaceutically acceptablesolvents, wherein said blend comprises diethylene glycol monoethyl etherand water in a weight ratio which increases the solubility of saidroflumilast relative to the solubility in water, wherein said diethyleneglycol monoethyl ether is in an amount sufficient to keep saidroflumilast dissolved after one month of storage, wherein saidroflumilast is in an amount of 0.05-0.5% by weight of the totalcomposition, wherein said composition does not contain undissolvedroflumilast before or after storage, and wherein said weight ratio ofdiethylene glycol monoethyl ether to water is 1:4 to 9:1.
 2. Thepharmaceutical composition according to claim 1, wherein said diethyleneglycol monoethyl ether is in an amount of 15-20% w/w.
 3. Thepharmaceutical composition according to claim 1, wherein saidroflumilast is in an amount of 0.05-0.3% w/w.
 4. The pharmaceuticalcomposition according to claim 1, wherein said pharmaceuticalcomposition is selected from the group consisting of an oil in wateremulsion, a thickened aqueous gel, a thickened hydroalcoholic gel, ahydrophilic gel, and a hydrophilic or hydrophobic ointment.
 5. Thepharmaceutical composition according to claim 1, wherein saidpharmaceutical composition further comprises at least one additionalcomponent selected from the group consisting of a solvent, moisturizer,surfactant or emulsifier, polymer or thickener, antifoaming agent,preservative, antioxidant, sequestering agent, stabilizer, buffer, pHadjusting solution, skin penetration enhancer, film former, dye,pigment, and fragrance.
 6. The pharmaceutical composition according toclaim 1, wherein said pharmaceutical composition further comprises anadditional active agent selected from the group consisting of Anthralin,Azathioprine, Tacrolimus, Coal tar, Methotrexate, Methoxsalen, Salicylicacid, Ammonium lactate, Urea, Hydroxyurea, 5-fluorouracil,Propylthouracil, 6-thioguanine, Sulfasalazine, Mycophenolate mofetil,Fumaric acid esters, Corticosteroids, Corticotropin, Vitamin Danalogues, Acitretin, Tazarotene, Cyclosporine, Resorcinol, Colchicine,Adalimumab, Ustekinumab, Infliximab, bronchodialators, and antibiotics.7. The pharmaceutical composition according to claim 1, wherein saidpharmaceutical composition comprises carriers suitable for topical,parenteral or pulmonary administration.
 8. The pharmaceuticalcomposition according to claim 7, wherein said pharmaceuticalcomposition comprises carriers suitable for topical administration. 9.The pharmaceutical composition according to claim 1, wherein saidpharmaceutical composition further comprises hexylene glycol in anamount of 0.1-20% w/w.
 10. A method for overcoming low aqueoussolubility of a roflumilast formulation, comprising combining diethyleneglycol monoethyl ether and water in a composition comprisingroflumilast, wherein said diethylene glycol monoethyl ether is in anamount of 10-30% (w/w), said water is in an amount of 20-90% (w/w) andsaid roflumilast is at a saturation concentration.
 11. The methodaccording to claim 10, wherein the ratio of diethylene glycol monoethylether to water is from 1:10 to 20:1.
 12. The method according to claim11, wherein said ratio of diethylene glycol monoethyl ether to water is1:4 to 9:1.
 13. The method according to claim 10, wherein saiddiethylene glycol monoethyl ether is in an amount of 15-20% (w/w). 14.The method according to claim 10, wherein said roflumilast compositioncomprises 0.005-2% roflumilast.
 15. A method of inhibitingphosphodiesterase 4 in a patient, comprising administering a compositioncomprising roflumilast and diethylene glycol monoethyl ether to saidpatient.
 16. The method according to claim 15, wherein said patient issuffering from an inflammatory condition.
 17. The method according toclaim 16, wherein said patient is suffering from atopic dermatitis.